title: Systems pharmacology of adverse event mitigation by drug combinations.
abstract: Drugs are designed for therapy, but medication-related adverse events are common, and risk/benefit analysis is critical for determining clinical use. Rosiglitazone, an efficacious antidiabetic drug, is associated with increased myocardial infarctions (MIs), thus limiting its usage. Because diabetic patients are often prescribed multiple drugs, we searched for usage of a second drug ("drug B") in the Food and Drug Administration's Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone ("drug A")-associated MI. In FAERS, rosiglitazone usage is associated with increased occurrence of MI, but its combination with exenatide significantly reduces rosiglitazone-associated MI. Clinical data from the Mount Sinai Data Warehouse support the observations from FAERS. Analysis for confounding factors using logistic regression showed that they were not responsible for the observed effect. Using cell biological networks, we predicted that the mitigating effect of exenatide on rosiglitazone-associated MI could occur through clotting regulation. Data we obtained from the db/db mouse model agreed with the network prediction. To determine whether polypharmacology could generally be a basis for adverse event mitigation, we analyzed the FAERS database for other drug combinations wherein drug B reduced serious adverse events reported with drug A usage such as anaphylactic shock and suicidality. This analysis revealed 19,133 combinations that could be further studied. We conclude that this type of crowdsourced approach of using databases like FAERS can help to identify drugs that could potentially be repurposed for mitigation of serious adverse events.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhao
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.forename: Yibang
authors.initials: Y
authors.lastname: Chen
authors.forename: Evren U
authors.initials: EU
authors.lastname: Azeloglu
authors.forename: Omri
authors.initials: O
authors.lastname: Gottesman
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.forename: Mohammad U
authors.initials: MU
authors.lastname: Zafar
authors.forename: Ludovic
authors.initials: L
authors.lastname: Benard
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Joseph
authors.initials: J
authors.lastname: Goldfarb
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D015986:Confounding Factors, Epidemiologic; D019992:Databases as Topic; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology; D004338:Drug Combinations; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000503:physiopathology / Q000517:prevention & control*; D000077270:Exenatide; D006334:Heart Function Tests; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D000077154:Rosiglitazone; D049490:Systems Biology; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use; D013916:Thrombelastography; D014463:Ultrasonography; D014481:United States; D014486:United States Food and Drug Administration; D014688:Venoms / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D004338:Drug Combinations; D010455:Peptides; D017395:Plasminogen Activator Inhibitor 1; D045162:Thiazolidinediones; D014688:Venoms; D000077154:Rosiglitazone; D000077270:Exenatide